The mammalian nervous system does not regenerate after injury despite the fact that there are many molecules present which encourage/promote axonal (nerve) growth. There are at least three factors that are responsible for this lack of regeneration: the formation of a glial scar, the presence of inhibitors of regeneration in myelin, and the intrinsic growth capacity of adult axons. In situations involving injury, the glial scar takes some time after injury to form. It would be advantageous to encourage axonal growth during this “window-of-opportunity”, before the scar forms. It would also be desirable to be able to encourage axonal growth irrespective of scarring, e.g., for treating or preventing neural degeneration or damage associated with a disorder, disease or condition. Blocking the function of the inhibitors of regeneration present in myelin can be achieved by, e.g., neutralizing the inhibitors or altering the growth capacity of the axon so that it no longer responds to the inhibitors.
To date, three inhibitors have been identified in myelin: myelin-associated glycoprotein (“MAG”) (McKerracher et al., Neuron 13:805-11 (1994); Mukhopadhyay et al., Neuron 13: 757-67 (1994); U.S. Pat. No. 5,932,542, U.S. Pat. No. 6,203,792, and U.S. Pat. No. 6,399,577; and WO 97/01352), Nogo (Chen et al., Nature 403:434-439 (2000); Grandpre et al., Nature 403:439-444 (2000)); and oligodendrocyte myelin glycoprotein (“Omgp”) (Wang et al., Nature 417:941-944 (2002)). All three of these inhibitors bind to Nogo-66 receptor (“NgR”) to exert their inhibitory effects (Wang et al., supra; Domeniconi et al., Neuron 35:283-290 (2002); Fournier et al., Nature 409:341-346 (2001); Liu et al., Science 297:1190-1193 (2002)).
It has been shown that by raising levels of a cyclic nucleotide called cyclic adenosine monophosphate (“cAMP”), one can reduce the inhibitory effects of MAG and significantly improve nerve fiber growth (WO 01/85981).